The overall goal of this project is to examine how the environmental aldehydes - acrolein and trans-2-hexenal enhance cardiovascular disease. Our central hypothesis is that environmental exposure these aldehydes accelerates atheroscterosis. We propose that the atherogenic effects of these aldehydes are in part due to their ability to modifying lipoproteins, induce vascular inflammation, and dysregulate cell growth. As a result, aldehyde exposure during on-going atherogenesis leads to the formation of more extensive, unstable, and acellular lesions. To test this hypothesis, in Specific Aim 1, we will examine the effects of inhaled acrolein or oral hexenal and acrolein on the rate and extent of formation of spontaneous atherosclerotic lesions in apoE-null mice, and the adhesiveness of the vascular endothelium. To elucidate the underlying molecular mechanisms, we will examine changes in the activation of the transcription factor NF-kappaB and the expression of inducible and soluble adhesion molecules ICAM-1 and VCAM-1. Experiments designed for Specific Aim 2 will delineate the contribution of dysregulated smooth muscle cell growth to the atherogenicity of aldehyde exposure. We will determine whether aldehyde exposure affects arterial stiffness, lesion cellularity, lipid core formation and the extent of macrophage and T-cell infiltration in the atherosclerotic plaques. In addition we will assess changes in the expression and activity of the transcription factor p53 and test whether this is affected by chronic aldehyde exposures. The third aim of our project is to elucidate aldehyde-mediated changes in lipoprotein metabolism. In this aim we will test the hypothesis that environmental exposure to aldehydes results in the inhibition of the thiol-sensitive enzyme lecthin:cholesterol acyl transferase (LCAT). Because this enzyme is involved in the maturation of the high-density lipoprotein (HDL) particle and the removal of cholesterol from peripheral organs, inhibition of LCAT leads a decrease in the levels of circulating HDL and increased deposition of cholesterol in peripheral tissues. To test this view, we will measure changes in lipoproteins, LCAT activity and tissue cholesterol content in exposed and non-exposed mice and determine whether the aldehyde-induced changes are enhanced in the apoE-null mice. Finally, we will determine whether inhibition of LCAT is due to direct covalent modification by the aldehydes and whether this leads to adaptive changes in the profiles of other lipoproteins. Together, our results will provide new information on the effects of the most toxic and ubiquitous pollutants on atherosclerosis, which is the leading cause of death in the industrialized world. These studies will provide direction for more in-depth investigations and form the basis of future assessment of human risk.